Splicing Modulation as Therapy for Human Genetic Disease

Abstract

The sequencing of the human genome has led to a greater appreciation of the contribution that genetic abnormalities and splicing errors make to the burden of human disease. The modulation of splicing using antisense oligonucleotides provides an attractive therapeutic option for tailored interventions in rare genetic disease. In this review, we outline the various approaches to splicing modulation and provide examples of each strategy. Finally, we address some of the practical issues facing the field in trying to bring this technology towards clinical application using the treatment of Duchenne muscular dystrophy and spinal muscular atrophy as examples. Key Concepts Ninety‐five percent of human genes undergo splicing. An estimated 50% of all human genetic diseases result from splicing abnormalities. Splicing modulation using antisense oligonucleotide (ASO) technology offers the future prospect of personalised medicine tailored to specific mutations. Strategies to modulate splicing include suppression of an aberrant splice isoform, switching between known splicing variants or generating a novel variant with a potential therapeutic attribute. ASO chemistries are varied and have been optimised to improve target binding and resist nuclease degradation. ASO targets include all pre‐mRNA sites which influence the splicing process. Splicing events can be complex and unpredictable. Therefore an iterative method of design and test is required to optimise ASO efficacy. ASO side‐effects are likely to stem from the ASO chemistry, off‐target effects as the result of nonspecific binding, and ASO distribution to organs when given in vivo. Optimising tissue delivery of ASO remains a significant challenge.